Showing papers by "Serpil C. Erzurum published in 2008"
TL;DR: It is concluded that air trapping is a characteristic feature of the severe asthma population, suggesting that there is a pathological process associated with severe asthma that makes airways more vulnerable to this component.
Abstract: Five to ten percent of asthma cases are poorly controlled chronically and refractory to treatment, and these severe cases account for disproportionate asthma-associated morbidity, mortality, and he...
286 citations
TL;DR: Mechanisms underlying pathological airway responses in severe asthma include lipoxin underproduction with decreased expression of lipoxin biosynthetic enzymes and receptors.
Abstract: Rationale: Airway inflammation is common in severe asthma despite antiinflammatory therapy with corticosteroids. Lipoxin A4 (LXA4) is an arachidonic acid–derived mediator that serves as an agonist for resolution of inflammation.Objectives: Airway levels of LXA4, as well as the expression of lipoxin biosynthetic genes and receptors, in severe asthma.Methods: Samples of bronchoalveolar lavage fluid were obtained from subjects with asthma and levels of LXA4 and related eicosanoids were measured. Expression of lipoxin biosynthetic genes was determined in whole blood, bronchoalveolar lavage cells, and endobronchial biopsies by quantitative polymerase chain reaction, and leukocyte LXA4 receptors were monitored by flow cytometry.Measurements and Main Results: Individuals with severe asthma had significantly less LXA4 in bronchoalveolar lavage fluids (11.2 ± 2.1 pg/ml) than did subjects with nonsevere asthma (150.1 ± 38.5 pg/ml; P < 0.05). In contrast, levels of cysteinyl leukotrienes were increased in both asthm...
235 citations
TL;DR: In this article, the relative contribution of bone marrow-derived proangiogenic precursors and tissue-resident endothelial progenitors to vascular remodeling in idiopathic pulmonary arterial hypertension (IPAH) was evaluated.
Abstract: Vascular remodeling in idiopathic pulmonary arterial hypertension (IPAH) involves hyperproliferative and apoptosis-resistant pulmonary artery endothelial cells. In this study, we evaluated the relative contribution of bone marrow-derived proangiogenic precursors and tissue-resident endothelial progenitors to vascular remodeling in IPAH. Levels of circulating CD34 + CD133 + bone marrow-derived proangiogenic precursors were higher in peripheral blood from IPAH patients than in healthy controls and correlated with pulmonary artery pressure, whereas levels of resident endothelial progenitors in IPAH pulmonary arteries were comparable to those of healthy controls. Colony-forming units of endothelial-like cells (CFU-ECs) derived from CD34 + CD133 + bone marrow precursors of IPAH patients secreted high levels of matrix metalloproteinase-2, had greater affinity for angiogenic tubes, and spontaneously formed disorganized cell clusters that increased in size in the presence of transforming growth factor-β or bone morphogenetic protein-2. Subcutaneous injection of NOD SCID mice with IPAH CFU-ECs within Matrigel plugs, but not with control CFU-ECs, produced cell clusters in the Matrigel and proliferative lesions in surrounding murine tissues. Thus, mobilization of high levels of proliferative bone marrow-derived proangiogenic precursors is a characteristic of IPAH and may participate in the pulmonary vascular remodeling process.
168 citations
Cleveland Clinic1, MetroHealth2, Wake Forest University3, University of Wisconsin-Madison4, University of Texas Medical Branch5, Washington University in St. Louis6, Imperial College London7, National Jewish Health8, University of Virginia9, Harvard University10, Emory University11, University of Pittsburgh12
TL;DR: Modeling confirmed that measures of Arg bioavailabilty predict airflow obstruction only in severe asthma, and Unlike Fe(NO), Arg bioavailability is not a surrogate measure of inflammation; however, Arg bio availability is strongly associated with airflow abnormalities insevere asthma.
Abstract: Rationale: As the sole nitrogen donor in nitric oxide (NO) synthesis and key intermediate in the urea cycle, arginine and its metabolic pathways are integrally linked to cellular respiration, metabolism, and inflammation. Objectives: We hypothesized that arginine (Arg) bioavailability would be associated with airflow abnormalities and inflammation in subjects with asthma, and would be informative for asthma severity. Methods: Arg bioavailability was assessed in subjects with severe and nonsevere asthma and healthy control subjects by determination of plasma Arg relative to its metabolic products, ornithine and citrulline, and relative to methylarginine inhibitors of NO synthases, and by serum arginase activity. Inflammatory parameters, including fraction of exhaled NO (FENO), IgE, skin test positivity to allergens, bronchoalveolar lavage, and blood eosinophils, were also evaluated. Measurements and Main Results: Subjects with asthma had greater Arg bioavailability, but also increased Arg catabolism compared with healthy control subjects, as evidenced by higher levels of FENO and serum arginase activity. However, Arg bioavailability was positively associated with FENO only in healthy control subjects; Arg bioavailability was unrelated to FENO or other inflammatory parameters in severe or nonsevere asthma. Inflammatory parameters were related to airflow obstruction and reactivity in nonsevere asthma, but not in severe asthma. Conversely, Arg bioavailability was related to airflow obstruction in severe asthma, but not in nonsevere asthma. Modeling confirmed that measures of Arg bioavailabilty predict airflow obstruction only in severe asthma. Conclusions :U nlike FENO, Arg bioavailability is not a surrogate measure of inflammation; however, Arg bioavailability is strongly associated with airflow abnormalities in severe asthma.
126 citations
TL;DR: Patients with IPAH have higher circulating levels of HA, and PASMCs derived from IPAH lungs produce more HA compared with controls, suggesting a role for HA in remodeling and inflammation in IPAH.
Abstract: Hyaluronan (HA), a large glycosaminoglycan found in the ECM, has major roles in lung and vascular biology and disease. However, its role in idiopathic pulmonary arterial hypertension (IPAH) is unkn...
87 citations
TL;DR: It is hypothesized that IFN‐γ is not critical in host survival because influenza A virus has mechanisms to evade the antiviral activity of IFN •γ through effects on the intracellular signaling pathways.
Abstract: The innate immunity to viral infections induces a potent antiviral response mediated by interferons (IFN). Although IFN-gamma is detected during the acute stages of illness in the upper respiratory tract secretions and in the serum of influenza A virus-infected individuals, control of influenza A virus is not dependent upon IFN-gamma as evidenced by studies using anti-IFN-gamma Ab and IFN-gamma(-/-) mice. Thus, we hypothesized that IFN-gamma is not critical in host survival because influenza A virus has mechanisms to evade the antiviral activity of IFN-gamma. To test this, A549 cells, an epithelial cell line derived from lung adenocarcinoma, were infected with influenza virus strain A/Aichi/2/68 (H3N2) (Aichi) and/or stimulated with IFN-gamma to detect IFN-gamma-stimulated MHC class II expression. Influenza A virus infection inhibited IFN-gamma-induced up-regulation of HLA-DRalpha mRNA and the IFN-gamma induction of class II transactivator (CIITA), an obligate mediator of MHC class II expression. Nuclear translocation of Stat1alpha upon IFN-gamma stimulation was significantly inhibited in influenza A virus-infected cells and this was associated with a decrease in Tyr701 and Ser727 phosphorylation of Stat1alpha. Thus, influenza A virus subverts antiviral host defense mediated by IFN-gamma through effects on the intracellular signaling pathways.
59 citations
TL;DR: A novel method for culturing murine trachea epithelial cells on a native basement membrane at an air-liquid interface to produce a pseudostratified, differentiated airway epithelium composed of ciliated and nonciliated cells was described.
44 citations
TL;DR: It is suggested that angiogenesis in the lungs may participate in the cyclic changes in gas transfer that occur over the menstrual cycle, and pulmonary vascularity is influenced by hormonal changes.
Abstract: Gas transfer in the female lung varies over the menstrual cycle in parallel with the cyclic angiogenesis that occurs in the uterine endometrium. Given that vessels form and regress in the uterus under the control of hormones, angiogenic factors, and proangiogenic circulating bone marrow-derived progenitor cells, we tested the possibility that variation in pulmonary gas transfer over the menstrual cycle is related to a systemic cyclic proangiogenic state that influences lung vascularity. Women were evaluated over the menstrual cycle with weekly measures of lung diffusing capacity and its components, the pulmonary vascular capillary bed and membrane diffusing capacity, and their relation to circulating CD34(+)CD133(+) progenitor cells, hemoglobin, factors affecting hemoglobin binding affinity, and proangiogenic factors. Lung diffusing capacity varied over the menstrual cycle, reaching a nadir during the follicular phase following menses. The decline in lung diffusing capacity was accounted for by approximately 25% decrease in pulmonary capillary blood volume. In parallel, circulating CD34(+)CD133(+) progenitor cells decreased by approximately 24% and were directly related to angiogenic factors and to lung diffusing capacity and pulmonary capillary blood volume. The finding of a greater number of lung microvessels in ovariectomized female mice receiving estrogen compared with placebo verified that pulmonary vascularity is influenced by hormonal changes. These findings suggest that angiogenesis in the lungs may participate in the cyclic changes in gas transfer that occur over the menstrual cycle.
17 citations